Additional supervisory team: Dr Paul Race, School of Biochemistry and Prof Chris Willis, School of Chemistry.

We are looking for outstanding students with a passion for research at the interface of chemistry and biology for a fully funded 4-year SWBio PhD studentship (fees and stipend at the standard rate). The project is available from September 2018 for candidates that satisfy BBSRC & SWBio DTP studentship eligibility requirements (see https://www.swbio.ac.uk/programme/eligibility/ if you are unsure). 

Our laboratories have a long-standing interest in the use of computational, biophysical and chemical methods to understand and manipulate biosynthesis. For this project, the aim is to develop ways to control how polyketide synthases, an important class of natural biocatalytic machinery, set the stereochemistry of their products, polyketides, many of which have antibiotic and/or anticancer activities. This will be done by modifying – or redesigning – a key enzyme in polyketide synthase systems that sets stereochemistry in the polyketide product chain, a ketoreductase. In particular, in the so-called polyketide synthase type II systems, an acyl-carrier protein (ACP) will bring the evolving polyketide chain to a ketoreductase, which will subsequently set a stereochemical center. Existing structural information defines how the ACP and the ketoreductase involved in making the polyketide actinorhodin (a natural antibiotic) will guide the development of computational prediction protocols. This will be the bulk of the work, involving QM/MM reaction simulations, molecular dynamics and protein-protein docking. The simulations will predict new ketoreductase variants that alter the stereochemical outcome. To test and improve these computational predictions, experimental characterisation of promising enzyme variants (product outcome, kinetics and structural biology) will be performed. Once successful, the atomic detail of new variants will be confirmed through structural biology techniques (NMR, X-ray crystallography). 

This interdisciplinary project is thus combining the expertise in computational simulation of enzymes in Bristol and the expertise from an internationally leading academic team with multidisciplinary expertise of polyketide systems and the relevant experimental techniques (enzymology, molecular biology, chemistry and structural biology).